tbuckley/cabot-search huggingface dataset:
Abstract 2134: Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer
Authors: Sung Uk Bae, Woon Kyung Jeong, Seong Kyu Baek
Journal: Cancer Research (2023)

Abstract Background: The impact of adjuvant chemotherapy for patients with stage II colon cancer has been addressed in several clinical trials. NCCN guideline recommends that patients with stage II disease that is MSS/pMMR and at high risk for systemic recurrence can be considered adjuvant chemotherapy. However, research on whether these high-risk features or status of microsatellite instability (MSI) are predictive markers for adjuvant chemotherapy (ACT) is insufficient. Materials and Methods: We assessed the efficacy of ACT and possible interaction with MSI status and high-risk features for recurrence in patients with resected stage II colon diagnosed at 16 tertiary referral hospitals between January 2010 and December 2017. Results: According to MSI status, 394 patients (21.8%) had MSI-high tumors and 1416 (78.2%) had MSI-low or microsatellite stable (MSS) tumors. There were 881 patients (48.7%) with one or more high-risk feature for recurrence. Among 161 patients with MSI-high and high-risk features, the 5-year disease-free survival (DFS) and overall survival (OS) of patients who received no ACT, 5-FU chemotherapy, and oxaliplatin-based chemotherapy were 65.5% and 72.3%, 89.4% and 97.9%, and 88.2% 92.0%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.972 and p=0.233, Oxaliplatin vs. no chemotherapy, p=0.016 and p=0.032, 5-FU vs. no chemotherapy, p=0.025 and p=0.003, respectively). Among 720 patients with MSI-low or MSS and high-risk features, the 5-year DFS and OS of patients who received no ACT, 5-FU, and oxaliplatin-based were 77.1% and 87.2%, 90.4% and 95.6%, and 86.9% 93.5%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.580 and p=0.492, Oxaliplatin vs. no chemotherapy, p=0.037 and p=0.077, 5-FU vs. no chemotherapy, p=0.009 and p=0.012, respectively). In patients without risk factors, there was no benefit from ACT regardless of MSI status. Conclusions: 5-FU chemotherapy can be recommended in patients with one or more high-risk features for recurrence regardless of MSI status in stage II colon cancer. Keyword: Colonic Neoplasms, Adjuvant Chemotherapy, Microsatellite Instability, Risk Factors Citation Format: Sung Uk Bae, Woon Kyung Jeong, Seong Kyu Baek. Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2134.
Abstract 5083: Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer
Authors: Bryan Jian Wei Lim, Xiao-Fan Wang, Qi-Jing Li
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype that makes up 10-20% of all breast cancer cases. Because of the higher risk of metastasis and recurrence post-treatment, there is a need to develop novel therapeutics to address these challenges. In previously published work, we demonstrated that CXCL16 traps CXCR6+PD-1+ effector/effector memory (TEFF/EM) within the primary tumor and that these T cells have anti-metastatic function that can be harnessed when released into peripheral sites with intra-tumoral administration of anti-CXCL16 prior to surgical resection. However, whether CXCL16 blockade can be used in combination with conventional checkpoint targets and the developmental route of this CXCR6+ TEFF/EM is not known. To develop a novel neoadjuvant therapy, we use the spontaneously metastasizing murine TNBC model, 4T1. Here, we report that anti-4-1BB, and not anti-PD-1, when used in combination with blockade of CXCL16 can prolong survival post-surgical resection. Using anti-4-1BB in combination with CRISPR-generated Cxcl16-KO 4T1 model, we show that both deficiency of CXCL16 within the tumor microenvironment (TME) and anti-4-1BB contribute synergistically to survival advantage. To study the development of this population of T cells, we use the Py8119 murine TNBC model. We definitively show that CXCR6+PD-1+ TEFF/EM is uniquely generated within the primary tumor. Co-expression of CXCR6 and PD-1 indicates that T cell receptor (TCR) signaling is a potential regulator of the development of this TEFF/EM sub-population. Analyses of our previously published scRNA-seq dataset reveals Lat2 to be the top gene involved in TCR signaling. Tumors growing on Lat2-KO animals show a significant increase in tumor size accompanied by significant reduction of CD44high/mid CXCR6+PD-1+ TEFF/EM. However, competitive transfer of naïve WT and Lat2-KO T cells into Tcra-KO recipients led to comparable levels of CXCR6+ TEFF/EM. Surprisingly, transferred Lat2-KO T cells failed to engraft within the primary tumor relative to WT T cells. Future work will address if this engraftment defect is due to expansion/survival defects. Therefore, regulation of TCR signaling within the TME via LAT2 potentially represents a mechanism in which primary tumors trap T cells, promoting their exhaustion. Importantly, this can be harnessed through combinatorial activation and blockade of 4-1BB and CXCL16 respectively. Citation Format: Bryan Jian Wei Lim, Xiao-Fan Wang, Qi-Jing Li. Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5083.
Abstract 6273: CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting <i>MTAP</i>-deleted human tumors
Authors: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu
Journal: Cancer Research (2023)

Abstract MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors. Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.
Abstract 5138: Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes
Authors: Julio C. Valencia, Michael Sanford, Howard A. Young
Journal: Cancer Research (2023)

Abstract The overlapping signatures of type 1 interferons (IFN) and IFN-gamma (IFNg) has proven challenging in human autoimmunity and cancer immunotherapy, particularly for resistance to anti-programmed death 1 (anti-PD1) monotherapy. By contrast, agonist abs targeting of CD40 (anti-CD40) antibodies (abs) has clinically elicit anti-tumor immunity with limited autoimmune complications. Here, we explore the relationships between anti-PD1 or agonist CD40 responses in melanoma tumors from type 1 IFN alpha receptor (IFNAR)-sufficient and type 1 IFNAR-deficient lupus-prone mice that overexpress IFNg. To address this, RNA-sequencing (RNA-seq) data on tumors treated with either anti-PD1 or agonist anti-CD40 was evaluated for tumor objective responses compared to untreated controls. Cellular and canonical pathway identification from RNA-seq data were interrogated from the IPA library for significantly differential expressed genes (DEG). Variance patterns of the anti-PD1 and anti-CD40 monotherapies identified known resistance and response pathways highly concordant with IFN co-expression patterns in the RNA-sequencing data, respectively. IPA biomarker analysis for uniquely regulated genes showed that anti-PD1 induced only 59 DEG; while anti-CD40 induced 494 DEG including Il-27, and PR/SET Domain 1 (PRDM1), a transcription factor regulated by IL-27. Specifically, signatures of MDSC development (irf8, il10); and adaptive resistance (pdcd1, pdcd1lg2, and TNFRSF5/CD40)) were negatively associated with response to anti-P1 monotherapy. By contrast, signatures of IFN activation (stat1, Ifng, and Ifngr1), chemotaxis (Cxcl10, Il12b and Il-27), attractants (Sema3g and Sema4a), and antigen presentation MHC II (h2-Aa, h2-Ab1, and ciita) were associated positively with response to agonist anti-CD40 monotherapy. Importantly, anti-CD40 alone delivered anti-tumor immune responses in type 1 IFN receptor-deficient lupus-prone mice that overexpress IFNg (Ifnar-/-ARE-/-) mice suggesting synergy with therapies blocking type 1 IFN signaling. Thus, these findings indicate that the rational use of CD40 agonists abs provide a better therapeutic platform to deliver precise anti-melanoma responses in complex autoimmune landscapes. Citation Format: Julio C. Valencia, Michael Sanford, Howard A. Young. Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5138.
Abstract 6607: Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision oncology
Authors: Kelli Goodman, Megan R. Showalter, Anne M. Evans, Matthew W. Mitchell, Rangaprasad Sarangarajan
Journal: Cancer Research (2023)

Abstract The COVID19 pandemic accelerated opportunities for innovation within the decentralization process of clinical trials with opportunities for implementation of patient-centric workflows for efficiency and cost-reduction. Decentralized sample collection, particularly whole blood using dried blood spots (DBS) provides the ideal mechanism for patient driven sample collection with ease of access to sample generation, drug level assessments and metabolomic prMegofiling, providing longitudinal real-time measure of drug specific pharmacodynamic readout for safety and efficacy. In this study, we report the development of a protocol for the capture and comprehensive profiling of metabolomics using dried blood spots from a cohort of 49 healthy volunteer donors. Using liquid chromatography combined with mass spectrometric (UPLC-MS/MS) methods an untargeted metabolomic approach resulted in the identification of &amp;gt;800 biochemicals of which a significant subset was found to be presented in corresponding matched plasma (from whole blood) samples. The biochemicals identified from the DBS samples included metabolites that were part of the lipid, amino acid, nucleotide, peptide, cofactors, carbohydrate and energy super pathways. A significant number of metabolites identified in the DBS samples were xenobiotics including those representing the biotransformation products of drugs. The overall metabolite profiles were analyzed for precision and accuracy of measure, variability in performance and dynamic range to establish benchmarks for evaluation. An additional cohort with a longitudinal sampling as part of the protocol provided the reproducibility of the analytic method for inter-day variability of metabolite performance over time. Although metabolomic profiles varied between individuals from a population perspective, there was minimal variation observed within individuals when samples were profiled longitudinally over several weeks. Thus, the protocols for DBS collection and the corresponding capture of a large set of metabolites with reproducible performance provides an opportunity for its implementation in oncological clinical trials as part of a de-centralized clinical trial solution. Citation Format: Kelli Goodman, Megan R. Showalter, Anne M. Evans, Matthew W. Mitchell, Rangaprasad Sarangarajan. Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6607.
Abstract 3555: Proteomic characterization of rhabdomyosarcoma-derived extracellular vesicles reveals a fusion-positive protein signature
Authors: Paula R. Quaglietta, Ashby Kissoondoyal, Ethan Malkin, David Malkin, Reto M. Baertschiger
Journal: Cancer Research (2023)

Abstract Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. Current diagnostic methods involve imaging and tissue biopsy for staging, histology and fusion status assessment. There are presently no serum biomarkers for rhabdomyosarcoma diagnosis or surveillance. Novel approaches and identification of biomarkers are warranted for minimally invasive diagnostic/surveillance techniques. Extracellular vesicles (EVs) are recognized as critical mediators of intercellular communication and the pathophysiology of carcinogenesis and metastasis. This study aimed to characterize the proteome of rhabdomyosarcoma-derived EVs and identify proteomic signatures that correlate with clinical characteristics such as histological subtype, cancer stage, age and metastasis, using patient-derived cell lines. EVs were isolated from cell culture conditioned media by differential ultracentrifugation from four rhabdomyosarcoma cell lines (RH4, RH18, RH30, RD), each in triplicate. Liquid chromatography-tandem mass spectrometry identified EV protein cargo. Proteins identified in our samples were compared to all available EV data in the Vesiclepedia database, using the FunRich software. We identified 1,527 total proteins in our rhabdomyosarcoma-derived EVs. When comparing to Vesiclepedia, 96 unique proteins were identified from our EVs that were not previously annotated in EVs within the database. Expression of these 96 proteins was further evaluated based on clinical characteristics of the tumors the cell lines were derived from. We found a four-protein signature in the EV secretome of rhabdomyosarcoma cell lines correlated with FOXO1 fusion-positive status. This signature includes proteins involved in regulating extracellular matrix organization, regulating gene expression, protein biosynthesis and translation. Rhabdomyosarcoma cells secrete EVs with unique protein cargo based on clinical characteristics of the parent tumor such as histological subtype and FOXO1 fusion status. Further validation of these secreted EV proteins in biological fluids could prove an effective liquid biopsy technique for novel diagnostic approaches or surveillance in pediatric rhabdomyosarcoma. Citation Format: Paula R. Quaglietta, Ashby Kissoondoyal, Ethan Malkin, David Malkin, Reto M. Baertschiger. Proteomic characterization of rhabdomyosarcoma-derived extracellular vesicles reveals a fusion-positive protein signature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3555.
Abstract 2314: Development of a 6-color multiplex Crystal Digital PCR assay for the detection of ESR1 and PIK3CA mutations in the plasma of metastatic breast cancer patients
Authors: Veronique Quillien, Julien Corne, Thibault De la Motte Rouge, Fanny Le Du, Florence Godey
Journal: Cancer Research (2023)

Abstract Blood-based liquid biopsies have become a real asset for patient treatment management in the field of precision oncology over the past few years, as they allow quick and easy access to tumor genetic alterations of interest. The analysis of circulating tumor DNA (ctDNA) from these liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of patients. In patients with HR+/HER2- metastatic breast cancer (MBC), early detection of ESR1 and PIK3CA mutations is a key element to better personalize disease management. Among the technologies currently used for liquid biopsies, digital PCR (dPCR) has the advantage of being among the fastest and least expensive, providing robust results along with unmatched sensitivity as compared to other methods. Until recently, however, dPCR has been previously limited by multiplex capability. The recent availability of the 6-color version of the naica® platform (Stilla Technologies) has allowed us to develop a single-well multiplexed assay that combines an 11 pathogenic mutation ESR1 assay with a 21 mutation PIK3CA assay, for a combined total of 32 ESR1 and PIK3CA mutations. Here we present data on this new high-plex dPCR panel. As ESR1 and PIK3CA analyses are often requested together, this new screening assay represents a significant saving of time and resources for the analysis of our MBC patients with a relative ease of implementation and analysis. Citation Format: Veronique Quillien, Julien Corne, Thibault De la Motte Rouge, Fanny Le Du, Florence Godey. Development of a 6-color multiplex Crystal Digital PCR assay for the detection of ESR1 and PIK3CA mutations in the plasma of metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2314.
Abstract 3441: A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity
Authors: Justine Habault, Jeffrey A. Schneider, Susan Ha, Rachel Ruoff, Joseph Puccini, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R. Wise, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian
Journal: Cancer Research (2023)

Abstract Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance despite the continued expression and function of the AR. We developed a new approach to antagonize the proliferative activity of AR and inhibit castration-resistant prostate cancer (CRPC) growth using multivalent peptoid conjugates (MPCs). Our strategy is to display multiple copies of the AR antagonist, ethisterone, on a peptoid scaffold. Such a multivalent display increases the ligand’s effective local concentration, thus targeting AR with high affinity and affecting AR interactions with coregulators. Here, we report a new potent MPC called MPC309, which displays three ethisterone groups and binds to AR with nanomolar affinity. MPC309 reduces the proliferation of enzalutamide-resistant prostate cancer cells, including those harboring AR splice variants, AR ligand binding mutations, and non-canonical AR gene expression programs. We provide evidence that MPC309 enters cells via macropinocytosis, which facilitates the fluid-phase uptake of extracellular macromolecules. Macropinocytotic uptake of MPC309 enhances cancer cell-specific delivery, thus limiting systemic toxicities. MPC309 displays favorable pharmacological properties and produced significantly greater tumor suppression in xenograft studies than enzalutamide, the standard of care anti-androgen in clinical use. Mechanistically, MPC309 inhibits prostate cancer growth by eliciting a unique gene expression program through alterations in AR chromatin occupancy compared to dihydrotestosterone (DHT) or enzalutamide. Thus, MPC309 represents a novel AR antagonist that activates an AR anti-proliferative program to repress the growth of CRPC and supports further investigation of the MPC compound class for treating CRPC. Citation Format: Justine Habault, Jeffrey A. Schneider, Susan Ha, Rachel Ruoff, Joseph Puccini, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R. Wise, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian. A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3441.